One-pot four-component synthesis of novel isothiourea-ethylene-tethered-piperazine derivatives

An efficient metal-free four-component approach for the synthesis of piperazine derivatives tethered to an isothiourea group through an ethylene link was developed. 1,4-Diazabicyclo[2.2.2]octane (DABCO) salts, generated in situ through the reactions of DABCO with various alkyl bromides, reacted with phenylisothiocyanate (PITC) and amines in a one-pot manner to give the target products. Initially, through two parallel nucleophilic paths, DABCO and the secondary amine adds to the alkyl bromide and PITC, respectively. The process is followed by the combination of the two respective intermediates to produce the final products by forming a new C–S bond with the expense of a C–N bond cleavage. Consequently, various DABCO salts and secondary amines were tolerated well in this protocol to afford the isothiourea-ethylene-tethered-piperazine compounds in good to high yields.


Introduction
Multicomponent reactions (MCRs) have emerged as a promising synthetic strategy in organic chemistry in recent decades, since they furnish one-pot routes to convert commercially available reactants to complex structures. 1,2In addition, MCRs are attractive from economical, operational simplicity, and green chemistry points of view. 3,4][9] However, earlier MCRs oen involved the use of limited starting materials, higher reaction temperatures, and toxic reagents.Thus, there is an ongoing demand for further improvement of MCRs by designing new processes with lower overall costs, better selectivity, higher efficiency, enhanced environmental aspects, and improved atom-economy.
Molecules containing isothiourea moieties constitute important structures in medicinal, 10,11 biological, 12,13 and agricultural chemistry. 14,15In addition, they are also employed as catalysts 16,17 or reactive intermediates 18 in other synthetic procedures.Illustrative related structures are highlighted in Fig. 1.Various methods are reported so far for the synthesis of these molecules.The majority of these reports are carried out using conventional stepwise approaches, 19,20 while a few recent studies deal with three-component procedures.For instance, Sun et al. developed a three-component synthesis of isothioureas via the combination of isocyanides and amines with disuldes, where the latter component was initially activated by N-halogen succinimides using (2,2,6,6-tetramethylpiperidin-1yl)oxyl (TEMPO). 21Alternatively, Maes devised a copper(I) catalyzed three-component reaction between thiosulfonates, amines, and isocyanides, resulting in the synthesis of isothiourea derivatives. 22Other important related reports include a tandem process by Wu, 23 a three-component reaction by Mishra, 24 and a binuclear aluminium complex mediated synthesis of carbodiimides by Panda. 25espite all the studies carried out on isothioureas, many traditional methods suffer from the use of complicated steps, toxic reagents or additives, and poor reactivity of the starting materials.Therefore, there is a need for further development of efficient and sustainable synthetic methods involving isothiourea chemistry.In the framework of our program on MCRs 26,27 and heterocyclic chemistry, 28,29 we would like to report a novel four-component procedure for the synthesis of a new series of isothiourea containing piperazines, as exemplied in Scheme 1 for the reaction of diethylamine (Et 2 NH), phenyl isothiocyanate (PITC), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1-bromo-2-methylpropane.
Although the use of DABCO bond cleavage for the synthesis of various piperazine derivatives has precedence, [30][31][32] the current work is the rst application of DABCO salts in the synthesis of the isothiourea functional group.For this purpose, we planned to use two very reactive species, the electrophilic isothiocyanate (PITC) moiety and the sterically hindered tertiary amine (DABCO), whose reactive natures can trigger parallel nucleophilic combinations of the reactants, which is a useful tool for launching multicomponent reactions.Consequently, this leads to a concurrent C-N bond cleavage and C-S bond formation reactions to produce the target products, in which RSC Advances PAPER the isothiourea and piperazine functional groups are placed in vicinity and would be interesting candidates for further biological studies.

Results and discussion
For simplicity, we rst synthesized the DABCO salts 2 separately to start the study with a three-component process.Thus, to optimize the reaction, we subjected Et 2 NH 1a and PITC to combine with 2a under various conditions (Table 1).Treatment of a 1.0 : 1.0 : 1.0 mixture of the three reactants and K 2 CO 3 at reuxing temperature in THF aer 5 h led to the formation of 3a in 93% yield (entry 1).In the absence of the base (entry 2) or at lower temperatures (entries 3-4), the yield was diminished even at a longer reaction time.Similarly, use of other inorganic bases (entries 5-8) did not led to higher conversion of the reactants to 3a.Alternatively, no better results were achieved for conducting the reaction in other protic (entries 9-11) or aprotic (entries 12-16) solvents, conveying that K 2 CO 3 /THF/reux conditions would provide the highest conversion of the reactants to the desired product.
With these results in hand, next we extended the process into a four-component combination by primarily subjecting DABCO to react with various alkyl bromides to provide the required salts 2 for the following steps (Table 2).Consequently, when DABCO, Me 2 CHCH 2 Br, Et 2 NH, and PITC were reacted in this manner, 3a was produced aer 12 h in 91% yield (entry 1).By using this approach, Et 2 NH and PITC reacted with other in situ generated derivatives of 2 to give 3b-e efficiently (entries 2-5).Similarly, products 3f-j were obtained in the same manner to emphasize the generality of the process (entries 6-10).
Based on these results, a mechanism would be proposed for this process.Initially, DABCO is alkylated via a nucleophilic attack on the alkyl bromide moiety to produce 2, while in a parallel reaction, Et 2 NH adds to PITC.The two resulting intermediates of the initial steps then would combine through K 2 CO 3 -activated attack of the diethyl-phenylthiourea species to the DABCO salt to access to the nal products.The stereochemistry of the isothiourea functional group was assigned as Z (as seen in Fig. 2 (top) for the product with R = Et and R ′ = Fig. 1 Important molecules containing the isothiourea functional group.
Scheme 1 One-pot four-component approach for the synthesis of isothiourea-ethylene-tethered piperazine derivatives.Paper RSC Advances CH 2 Ph).Such assignment for similar molecules resulting from the same chemistry is reported before in the literature. 15,33To further support the assignment, we engaged molecular mechanics calculations to verify the proposed stereochemistry.
The results arising from molecular mechanics (MM2) calculations using ChemSo's ChemOffice Pro (version 20) clearly show that the Z conguration (Fig. 2, bottom-le) is more stable that the E counterpart (Fig. 2, bottom-right).

Experimental
General FT-IR spectra were recorded using KBr disks on a Bruker Vector-22 spectrometer.NMR spectra were obtained on a Bruker AMX (300 MHz for 1 H and 75 MHz for 13 C) as CDCl 3 solutions using TMS as internal standard reference.Elemental analyses were performed using a Thermo Finnigan Flash EA 1112 instrument.
MS spectra were obtained on a Fisons 8000 Trio instrument at ionization potential of 70 eV.TLC experiments were carried out on pre-coated silica gel plates using petroleum ether/EtOAc as the eluent.Starting materials and reagents were purchased from commercial sources.

Synthesis of ammonium salts 2a from DABCO
To a solution of DABCO (1.12 g, 10.0 mmol) in THF (20 mL) was added Me 2 CHCH 2 Br (10.0 mmol), and the solution was stirred at room temperature for 12 h.A precipitate was formed, which was ltered, washed with ethyl acetate (10 mL) and dried under vacuum to get 2a.

Typical procedure for three-component synthesis of functionalized piperazines 3a
A mixture of 2a (0.11 g, 0.5 mmol), Et 2 NH (57.0 mL, 0.55 mmol), PITC (0.07 g, 0.5 mmol), and K 2 CO 3 (0.069 g, 0.5 mmol) in THF (5 mL) was stirred at reuxing temperature for 5 h.Aer completion of the reaction, the solvent was evaporated under vacuum and the concentrated crude mixture was fractionated by column chromatography on silica gel (EtOAc/petroleum ether; 60/40) to afford the pure product.The isolated product was fully characterized by various spectroscopic methods.

Typical procedure for four-component synthesis of functionalized piperazines 3a
To a solution of DABCO (1.12 g, 10.0 mmol) in THF (30 mL) was added Me 2 CHCH 2 Br (10.0 mmol), and the solution was stirred at room temperature for 12 h to get 2a.To this was added Et 2 NH (1140 mL, 10.0 mmol), PITC (1.4 g, 10.0 mmol), and K 2 CO 3 (1.4g, 10.0 mmol) in THF (10 mL) and the mixture was stirred at reuxing temperature for 5 h.Aer completion of the reaction, the solvent was evaporated under vacuum and the concentrated crude mixture was fractionated by column chromatography on silica gel (EtOAc/petroleum ether; 60/40) to afford the pure product.The isolated product was fully characterized by various spectroscopic methods.

Fig. 2
Fig. 2 Proposed mechanism for the synthesis of the products (top) and configurational projection of MM2-energy-minimised 3e (bottom) obtained from ChemDraw Pro.